한빛사논문
- 조회688
Jinhyuk Choi1,*, Tae Gyu Oh2,*, Heewon Jung1, Kun-Young Park1, Hyemi Shin1, Taehee Jo1, Du-Seock Kang1, Dipanjan Chanda3,4, Sujung Hong1, Jina Kim5, Hayoung Hwang5, Moongi Ji6, Minkyo Jung7, Takashihoji8, Ayami Matsushima9, Pilhan Kim1, Ji Young Mun7, Man-Jeong Paik6, Sung Jin Cho5, In-Kyu Lee3,4,10,11, David C. Whitcomb12-14, Phil Greer12,13, Brandon Blobner13, Mark O. Goodarzi15, Stephen J. Pandol16,17, Jerome I. Rotter18,19, North American Pancreatitis Study 2 (NAPS2) consortium, Weiwei Fan2, Sagar P. Bapat2,20-22, Ye Zheng22, Chris Liddle23, Ruth T. Yu2, Annette R. Atkins2, Michael Downes2, Eiji Yoshihara2,24,25, Ronald M. Evans2, and Jae Myoung Suh1
1 Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
2 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
3 Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of Korea
4 Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu 41404, Republic of Korea
5 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
6 College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea
7 Department of Neural Circuits Research, Korea Brain Research Institute, Daegu 41068, Republic of Korea
8 Department of Medicine, Kyoto University, Kyoto 606-8501, Japan
9 Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka 819-0395, Japan
10 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Republic of Korea
11 Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41404, Republic of Korea
12 Ariel Precision Medicine, Pittsburgh, PA 15206, USA
13 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
14 Department of Cell Biology and Molecular Physiology and the Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
15 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, CedarsSinai Medical Center, Los Angeles, CA 90048, USA
16 Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
17 Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
18 The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
19 Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
20 Department of Laboratory Medicine, University of California-San Francisco, San Francisco, CA 94143, USA
21 Diabetes Center, University of California-San Francisco, San Francisco, CA 94143, USA
22 Nomis Laboratories for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
23 Storr Liver Centre, The Westmead Institute, University of Sydney, Westmead, NSW 2145, Australia
24 The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
25 David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
*These authors contributed equally.
Correspondence to Eiji Yoshihara, Ronald M. Evans, Jae Myoung Suh
Abstract
BACKGROUND & AIMS
Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.
METHODS
Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts.
RESULTS
Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis.
CONCLUSIONS
Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.
논문정보
- Research article
- 2022년 04월 (BRIC 등록일 2022-05-02)
- 국내(교신)+국외 연구진
- 의약학 > 분자세포의학
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